US4048155A - Process for preparing 7 α-alkoxycephalosporin derivatives - Google Patents

Process for preparing 7 α-alkoxycephalosporin derivatives Download PDF

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Publication number
US4048155A
US4048155A US05/627,111 US62711175A US4048155A US 4048155 A US4048155 A US 4048155A US 62711175 A US62711175 A US 62711175A US 4048155 A US4048155 A US 4048155A
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group
tert
methyl
carbon atoms
oxidizing agent
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US05/627,111
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Hiroaki Yanagisawa
Akiko Ando
Masami Fukushima
Hideo Nakao
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Sankyo Co Ltd
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Sankyo Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/18—7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/57—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with a further substituent in position 7, e.g. cephamycines

Definitions

  • This invention relates to a novel process for introducing an alkoxy group into the 7 ⁇ -position of 7-amino-3-cepehm-4-carboxylic acid derivative.
  • this invention relates to a process for the preparation of 7 ⁇ -alkoxy-3-cephem-4-carboxylic acid derivatives having the formula ##STR1## wherein R represents an alkyl group having 1-4 carbon atoms, R 1 represents hydrogen atom, methyl group, cyanomethyl group, an acyloxymethyl group, carbamoyloxymethyl group, an alkoxymethyl group, an alkylthiomethyl group or a heterocyclic thiomethyl group, R 2 , R 3 , R 4 and R 5 may be the same or different and each represents hydrogen atom, an alkyl group having 1-4 carbon atoms, an alkoxy group having 1-4 carbon atoms, a halogen atom, cyano group or a alkoxycarbonyl group having 1-4 carbon atoms in the alkoxy moiety, or R 2 and R 3 or R 4 and R 5 may be linked together to form a saturated, unsaturated or aromatic ring, n is an integer of 1 or 2 and Y + is
  • R is preferably a methyl group.
  • R 1 is preferably a hydrogen atom; methyl group; cyanomethyl group; an acyloxymethyl group such as an alkanoyloxymethyl group, e.g., acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl or an aroyloxymethyl group, e.g., benzoyloxymethyl; carbamoyloxymethyl group; an alkoxymethyl group such as methoxymethyl, ethoxymethyl and butyloxymethyl; an alkylthiomethyl group such as methylthiomethyl, ethylthiomethyl, propylthiomethyl; or a heterocyclic thiomethyl group such as 2-pyridylthiomethyl, 1-methyl-1H-tetrazol-5-ylthiomethyl, 2-(1,3,5-triazolo)thiomethyl, 3-pyrazolothiomethyl, 1-imidazolinylthiomethyl, 5-methyl-1,3,4-
  • the groups R 2 to R 5 may be the same of different and each represents preferably a hydrogen atom; a straight or branched alkyl group having 1-4 carbon atoms such as methyl, ethyl, propyl, isopropyl and tert.-butyl; a straight or branched alkoxy group having 1-4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy and tert.-butoxy; a halogen atom such as chlorine and bromine; cyano group; an alkoxycarbonyl group having 1-4 carbon atoms in the alkyl moiety such as methoxycarbonyl, ethoxycarbonyl and tert.-butoxycarbonyl.
  • R 2 and R 3 or R 4 and R 5 may be linked together to form a saturated, unsaturated or aromatic ring such as cyclopentane, cyclohexane, cycloheptane and benzene.
  • n is an integer of 1 or 2 and; when n is 2, for example, biphenyl, binaphthalene or p-(4-napthyl)benzene may be formed.
  • R 3 and R 4 may be suitably selected from a sterically hindered alkyl group such as isopropyl and tert.-butyl.
  • Y + is a cation suitably selected from the group consisting of an alkali metal ion and an ammonium ion having the formula ##STR2## wherein R a , R b , R c and R d may be the same or different and each represents hydrogen atom; a straight or branched alkyl group having 1-8 carbon atoms such as methyl, ethyl, propyl, isopropyl, tert.-butyl, octyl and tert.-octyl; a cycloalkyl group having 5-7 carbon atoms such as cyclopentyl, cyclohexyl and cycloheptyl; phenyl group; or a phenylalkyl group having 1-4 carbon atoms in the alkyl moiety such as benzyl or phenethyl; or R a and R b may be linked together with N to form a saturated heterocyclic ring such as pyr
  • Y + lithium, sodium, tert.-butylammonium, tert.-octylammonium, dicyclohexylammonium, diisopropylammonium, triethylammonium and trimethylbenzylammonium ions.
  • compounds represented by the above formula (I) can be prepared by oxidizing a 7-benzylideneamino-3-cephem-4- carboxylic acid derivative having the formula ##STR3## wherein R 1 , R 2 , R 3 , R 4 , R 5 , n and Y + are as defined above and reacting the resulting product with an alkanol having 1-4 carbon atoms.
  • the oxidation step may be conducted by contacting the compound (II) with an oxidizing agent in an appropriate solvent.
  • oxidizing agent there is no particular limitation if it can convert the phenol moiety in the benzylidene group into the corresponding quinoid form without any attack to the cephem nucleus.
  • an oxidizing agent include a metal oxide such as lead dioxide and manganese dioxide, a quinone derivative with a powerful oxidizing property such as dicyanodichlorbenzoquinone, a hypochlorite derivative such as tert.-butylhypochlorite in the presence of a base which produces a phenolate ion, or a halogen compound which possesses oxidizing power such as N-bormosuccinimide and N-chlorsuccinimide.
  • the solvent may be employed an aromatic hydrocarbon such as benzene and toluene, a halogenated hydrocarbon such as chloroform and methylene chloride and an ether such as dioxane and tetrahydrofuran.
  • the reaction may proceed in a stoichiometric amount of an oxidizing agent, but an excess amount of the reagent of about 1.1-10 times molar may be usually used for acceleration of the reaction.
  • the reaction temperature is not particularly critical and the reaction may be usually effected at room temperature, but the reaction may proceed at a higher or lower temperature.
  • the time required for the reaction may be varied mainly depending upon the starting material, the oxidizing agent, the sort of solvent, the reaction temperature, and the like, but it may usually take about 10 minutes to several tens of minutes.
  • the compound having the above-described general formula (II) which may be employed in the process of this invention may be prepared in situ by the interaction of a 7-aminocephalosporin compound with an aryl aldehyde prior to the practice of the process of this invention and used per se.
  • the product formed by the oxidation may be recovered in a usual manner.
  • the oxidizing agent is separated by filtration from the reaction mixture and the solvent is removed from the filtrate under a reduced pressure to give the product, which may be purified by a conventional method, e.g., column chromatography, but the filtrate per se may be employed without isolation and purification of the product as a solution of the starting material in the subsequent step according to the process of his invention.
  • the alkoxylation step may be easily conducted by contacting the product obtained above with the alkanol.
  • Representative examples of the alcohol include methanol, ethanol and propanol.
  • the reaction may proceed in a stoichiometric amount of the alkanol, but an excess amount of the alkanol of about 10-100 times molar may be usually used for the promotion of the reaction.
  • the rection temperature is not particularly critical and the reaction may be usually carried out at room temperature, but the reaction may proceed at a higher or lower temperature.
  • the time required for the reaction may be varied mainly depending upon the starting material, the kind of lower alkanol, the reaction temperature, and the like, but it may usually take about 0.5 to several hours.
  • the two steps in this invention can be preferably carried out simultaneously by reacting with an oxidizing agent in the presence of the alkanol.
  • the reaction may be easily carried out by the following procedure.
  • the lower alknaol employed in the reaction To a solution of the compound having the above-mentioned general formula (II) in a suitable solvent is added the lower alknaol employed in the reaction and subsequently adding the oxidizing agent, for instance, dicyanodichlorbenzoquinone or tert.-butylhypochlorite in the presence of a base.
  • the solvent which may be employed in this reaction there is no particular limitation if it will not participate in the reaction and various inert organic solvents may be used. As examples of such solvents may be mentioned, for instance, ether, tetrahydrofuran and the like.
  • the lower alkanol which is employed for the alkoxylation reaction may be also used as a solvent.
  • the oxidizing agent may be preferably used in a stoichiometric or a slight excess amount, and in case of using a halogenated compound as an oxidizing agent in e
  • the base which is employed in the reaction is a basic metal compound or a basic nitrogen compounds.
  • basic metal compounds may be exemplified, for instance, alkoxides such as lithium methoxide and the like.
  • tert.-amines for instance, DBU (1,8 -diazabicyclo [5.4.0]-7-undecene) may be preferably used.
  • Alkali metal alkoxides may be preferably used.
  • reaction temperature there is no particular limitation, but, in order to minimize occurrence of side reactions, a relatively low temperature may be preferable and the reaction may be preferably conducted under a room temperature or most preferably under 0° C.
  • the time required for the reaction may be varied mainly depending upon the sort of oxidizing agent, the sort of alcohol and the reaction temperature employed and the like, but it may usually take several minutes to several tens of minutes.
  • the alkoxylated compound may be recovered from the reaction mixture in a usual manner. For instance, the solvent and excess alkanol are removed from the reaction mixture to give an amorphous end product in this step, which may be then purified by conventional method, e.g., by recrystallization or column chromatography.
  • reaction can be carried out by conventional means and will be exemplified later.
  • reaction mixture was filtered and the filtrate was condensed under a reduced pressure to give a crystalline substance, which, after addition of isopropanol, was collected by filtration affording 45.03g of the desired product as white crystals melting at 183°-185° C with decomposition.
  • reaction mixture was stirred for 10 minutes at -15° C, then 100 mg of 2,6-di-tert.-butyl-p-cresol was added, and stirring was further continued at 0° C for 10 minutes.
  • Addition of 0.56 ml of triethylamine was made to the resulting reaction mixture, which was then condensed to about 10 ml, 5 ml of chloroform was added thereto and it was washed four times with the same volume of water.
  • reaction mixture was condensed to dryness under a reduced pressure, the residue dissolved in 100 ml of ethyl acetate, and the resulting solution was washed successively with aqueous 5% sodium hydrogen carbonate and water and dried over anhydrous sodium sulfate. Removal of the solvent under a reduced pressure gave 0.54g of tert.-octylammonium 7 ⁇ -methoxy-7 ⁇ -(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)-3-methyl3-cephem-4-carboxylate.
  • the residue was purified by a column chromotography using dried silica gel as an adsorbent and a mixture of methanol - chloroform (1:9) as a developing solvent to give 200 mg of lithium 7 ⁇ -methoxy-7 ⁇ -(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)-3-methyl-3-cephem-4-carboxylate as a pale yellow powder.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)
US05/627,111 1974-11-15 1975-10-30 Process for preparing 7 α-alkoxycephalosporin derivatives Expired - Lifetime US4048155A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP49131761A JPS5159890A (en) 1974-11-15 1974-11-15 77 arukokishisefuarosuhorinjudotaino seizoho
JA49-131761 1974-11-15

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US4048155A true US4048155A (en) 1977-09-13

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US (1) US4048155A (en, 2012)
JP (1) JPS5159890A (en, 2012)
CA (1) CA1059990A (en, 2012)
CH (1) CH618702A5 (en, 2012)
DE (1) DE2550867C2 (en, 2012)
DK (1) DK155671C (en, 2012)
FR (1) FR2291205A1 (en, 2012)
GB (1) GB1488068A (en, 2012)
NL (1) NL183650C (en, 2012)
SE (1) SE431210B (en, 2012)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090260438A1 (en) * 2008-04-22 2009-10-22 Hedtke Robert C Industrial process device utilizing piezoelectric transducer

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57188595A (en) * 1981-05-14 1982-11-19 Meiji Seika Kaisha Ltd 7alpha-methoxycephem compound and its preparation
EP0389176A3 (en) * 1989-03-18 1992-01-15 Beecham Group p.l.c. Beta-lactams and processes for their preparation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3775410A (en) * 1971-11-29 1973-11-27 B Christensen Process for preparing cephalosporin compounds
US3840532A (en) * 1972-05-01 1974-10-08 Lilly Co Eli Process for cleaving cephalosporin compounds
US3875146A (en) * 1971-04-30 1975-04-01 Merck & Co Inc Process to prepare intermediates for the preparation of cephalosporins and penicillins

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3843641A (en) * 1971-11-29 1974-10-22 Merck & Co Inc Process for preparing penicillin and cephalosporin compounds
YU36181B (en) * 1971-11-29 1982-02-25 Merck & Co Inc Process for obtaining 7-(2-thienylacetamido)-7-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylates
DE2221035C2 (de) * 1972-04-28 1982-03-25 Merck & Co., Inc., 07065 Rahway, N.J. Verfahren zur Herstellung von substituierten 6-Iminopenicillinen und 7-Iminocephalosporinen
JPS554115B2 (en, 2012) * 1973-09-07 1980-01-29
JPS557436B2 (en, 2012) * 1974-04-03 1980-02-25

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3875146A (en) * 1971-04-30 1975-04-01 Merck & Co Inc Process to prepare intermediates for the preparation of cephalosporins and penicillins
US3775410A (en) * 1971-11-29 1973-11-27 B Christensen Process for preparing cephalosporin compounds
US3840532A (en) * 1972-05-01 1974-10-08 Lilly Co Eli Process for cleaving cephalosporin compounds

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090260438A1 (en) * 2008-04-22 2009-10-22 Hedtke Robert C Industrial process device utilizing piezoelectric transducer

Also Published As

Publication number Publication date
JPS5159890A (en) 1976-05-25
FR2291205B1 (en, 2012) 1979-06-01
NL183650C (nl) 1988-12-16
FR2291205A1 (fr) 1976-06-11
SE431210B (sv) 1984-01-23
DE2550867C2 (de) 1984-08-23
CH618702A5 (en, 2012) 1980-08-15
NL183650B (nl) 1988-07-18
GB1488068A (en) 1977-10-05
DK515875A (da) 1976-05-16
NL7513423A (nl) 1976-05-18
JPS5521753B2 (en, 2012) 1980-06-12
DE2550867A1 (de) 1976-05-26
SE7512830L (sv) 1976-05-17
DK155671B (da) 1989-05-01
DK155671C (da) 1989-09-25
CA1059990A (en) 1979-08-07

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